This proposal is an extension of R37 AI027998, a MERIT award to Marc Jenkins to study the role of D28 family proteins in the provision of costimulatory signals to CD4+ T cells. Significant progress was made in the first 4 years of funding, resulting in 6 senior author paper and 2 middle author papers by Dr. Jenkins. Two of the senior author papers were published in Immunity, 2 in PNAS and 1 in Nature Immunology. These papers and one about to be submitted describe achievement of may ofthe goals of original Specific Aim 1 including development of a sensitive peptide:major histocompatibility complex II (p:MHCIl) tetramer-based cell enrichment assay to detect naive polyclonal p:MHCII-specific CD4+ T cells, validation ofthis assay as a means to monitor clonal expansion, contraction, and memory cell formation from naive p:MHCII-specific precursors during a physiologically relevant bacterial infection, use ofthis assay to show that the major function of CD28 in vivo is to sustain clonal expansion through a signaling pathway involving NFkB but independent of the 2 suspected motifs in the CD28 cytoplamic tail, and identification of the role of CD28 family protein Inducible Costimulator (ICOS) in the formation of central memory cells and follicular helper cells. Progress was also make in Specific Aim 2 including validation of p:MHCIl tetramer-based cell enrichment as a means to study tolerance within polyclonal self-reactive T cell populations in normal repertoires and identification of candidate self antigens of potential relevance to autoimmunity that develops in mice lacking the inhibitory CD28 family protein CTLA-4.
Aims forthe extension period include determination of whether CD28 signaling enhances TCR recruitment to the immune synapse in vivo and identification of MHCII-binding peptides in autoantigens from CTLA-4-deficient mice, production of p:MHCII tetramers containing these peptides, and use of these tetramers to determine if CTLA-4 controls autoimmunity by killing self pMHCII-specific T cells, making them anergic, or converting them into regulatory T cells.

Public Health Relevance

These studies are relevant because they focus on molecules (CD28, ICOS, and CTLA-4) that regulate the quality of the immune response by T lymphocytes. Several promising therapies based on blockade of these molecules are in use, or development for the treatment of arthritis, transplant rejection, and cancer. The plan described in this application is designed to further the understanding ofthe mechanisms by which these molecules control the immune response with the hope of improving the efficacy of the aforementioned treatments and extending them to other T cell-mediated diseases.

National Institute of Health (NIH)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Lapham, Cheryl K
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University of Minnesota Twin Cities
Schools of Medicine
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Tubo, Noah J; Pagan, Antonio J; Taylor, Justin J et al. (2013) Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153:785-96
Nelson, Ryan W; McLachlan, James B; Kurtz, Jonathan R et al. (2013) CD4+ T cell persistence and function after infection are maintained by low-level peptide:MHC class II presentation. J Immunol 190:2828-34
Pagán, Antonio J; Peters, Nathan C; Debrabant, Alain et al. (2013) Tracking antigen-specific CD4+ T cells throughout the course of chronic Leishmania major infection in resistant mice. Eur J Immunol 43:427-38
Jenkins, Marc K; Moon, James J (2012) The role of naive T cell precursor frequency and recruitment in dictating immune response magnitude. J Immunol 188:4135-40
Taylor, Justin J; Pape, Kathryn A; Jenkins, Marc K (2012) A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med 209:597-606
Pape, Kathryn A; Taylor, Justin J; Maul, Robert W et al. (2011) Different B cell populations mediate early and late memory during an endogenous immune response. Science 331:1203-7
Pepper, Marion; Pagan, Antonio J; Igyarto, Botond Z et al. (2011) Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35:583-95
Chu, H Hamlet; Moon, James J; Kruse, Andrew C et al. (2010) Negative selection and peptide chemistry determine the size of naive foreign peptide-MHC class II-specific CD4+ T cell populations. J Immunol 185:4705-13
Pepper, Marion; Linehan, Jonathan L; Pagan, Antonio J et al. (2010) Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat Immunol 11:83-9
Catron, Drew M; Pape, Kathryn A; Fife, Brian T et al. (2010) A protease-dependent mechanism for initiating T-dependent B cell responses to large particulate antigens. J Immunol 184:3609-17

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